Modafinil for the treatment of sleep apneas and ventilatory disorders of central origin

ABSTRACT

The present invention relates to the utilization of modafinil for the treatment of ventilation disorders of central origin such as sleep apnea.

The present invention relates to a new use in therapeutics of modafinil.

Modafinil or benzhydrylsulphinyl acetamide is a compound of formula:##STR1##

This compound and its therapeutic application as an agent which isactive with respect to the central nervous system have been described inPatent Application FR-A-2,385,693. This application describespharmacological properties showing waking and antidepressantpharmacological effects. Very favourable results are mentioned for thetreatment of asthenias in elderly people. The product is furthermoredescribed as useful in the treatment of tardive dyskinesias ofneuroleptics. Application FR-A-2,663,225 describes therapeuticproperties which are useful in the treatment of neurodegenerativediseases of the dopaminergic pathways of the central nervous system,such as Parkinson's disease. Moreover, French Patent Application 91 15534 describes properties which are useful in the treatment of sequel ofcerebral ischaemic accidents.

It has now been discovered that modafinil has a beneficial effect withrespect to apneas occurring during sleep apnea syndromes.

The subject of the present invention is consequently the use ofmodafinil for the manufacture of a medicament having a beneficial effecton the occurrence of the apneas which characterize sleep apneasyndromes, and more generally ventilatory disorders of central origin.

The anti-apnea medicament containing modafinil can be presented inparticular in a form suitable for oral administration. Generally, thedose administered can be from 1 mg/kg to 100 mg/kg.

It will be recalled that an apnea is defined as an interruption of thenasobuccal airflow exceeding a duration arbitrarily set at 10 seconds(Guilleminault C., Tilkian A., Dement W C.: Ann. Rev. Med., 1976, 27:465-484). Three types of apnea are to be distinguished: apneas ofcentral origin, apneas by obstruction of the airways, and apneas, knownas mixed apneas, combining the two central and obstructive causes. Sleepapnea syndromes are conventionally defined by an apnea number greaterthan 5 apneas per hour of sleep. More recently, the syndromes aredefined by an apnea and hypopnea number greater than 10 events per hourof sleep.

The result of a clinical trial demonstrating the anti-apnea effects ofmodafinil in man will be given below.

6 subjects, of both sexes, monitored in a specialist hospital departmentand suffering from sleep apnea syndrome of central and mixed origin wereincluded in a single-blind pilot clinical trial comparing the effect ofmodafinil with the usual treatments such as CIPAP. The patients werediagnosed by a polysomnographic recording method comprising theidentification of the sleep stages and the measurement of the durationof each stage, the detection of apneas and the measurement of theconsequences of these apneas on the arterial gasometric parameters, theheart rate and the arterial pressure. Identification of the sleep stageswas carried out using electroencephalographic (EEG), electromyographic(EMG) and electro-oculographic (EOG) recordings. Ventilatory activitywas determined using thermistors. Oxygen saturation of haemoglobin wasmeasured by transcutaneous oximetric measurement. Finally, the othergasometric parameters were measured using an automatic gas analyser ofCorning type. Clinical signs such as diurnal somnolence and the qualityof nocturnal sleep were assessed using a clinical assessment scale and asleep diary filled in by the patient and the clinical investigator.Modafinil was administered during the day, preferably in the morning andat the beginning of the afternoon.

The results unexpectedly report an effect on the number of nocturnalapneas occurring during sleep and hypopnea. This number significantlydecreases in 4 subjects out of 6 after 1 month of treatment and, in onesubject out of 6, the apneas disappear completely from the recordingsafter treatment. The improvement relating to the number of apneasoccurring during sleep seems to persist for several days afterinterruption of the treatment. The modafinil doses administered per daywere from 200 mg to 600 mg.

By way of example, the results obtained with one patient are presentedin Table I, which compares the results relating to the apneas before andduring the treatment with modafinil.

The treatment with modafinil contributed to improving diurnal somnolenceand the quality of nocturnal sleep.

The clinical results observed in man make it possible to envisage theapplication of the medicament in the treatment of sleep apneas and moregenerally to ventilatory disorders of central origin.

                  TABLE I                                                         ______________________________________                                                            Before During the                                                             treatment                                                                            treatment                                          ______________________________________                                        RESULTS RELATING TO THE APNEAS                                                TOTAL NUMBER OF APNEAS                                                                              368      3                                              Number of central apneas                                                                            269      2                                              Number of peripheral   59      1                                              apneas                                                                        Number of mixed apneas                                                                               40      0                                              TOTAL DURATION OF THE 7432 sec 35 sec                                         APNEAS                                                                        Total duration of the 5546 sec 23 sec                                         central apneas                                                                Total duration of the peri-                                                                          988 sec 12 sec                                         pheral apneas                                                                 Total duration of the mixed                                                                          898 sec  0 sec                                         apneas                                                                        OVERALL DISTRIBUTION OF THE APNEAS                                            APNEAS OF LESS THAN                                                           10 SECONDS                                                                    Number                 2       0                                              Total duration         18 sec   0 sec                                         Mean duration           9 sec   0 sec                                         Total duration/duration of                                                                           0.06%     0%                                           sleep                                                                         APNEAS EQUAL TO OR GREATER                                                    THAN 10 SECONDS                                                               Number                366      3                                              Total duration        7414 sec 35 sec                                         Mean duration          20 sec  12 sec                                         Total duration/duration of                                                                          26.23%   0.15%                                          sleep                                                                         APNEA NUMBER          46.62    0.45                                           APNEA RATE            26.3%    0.15%                                          ______________________________________                                    

I claim:
 1. Process for the treatment of ventilatory disorders ofcentral origin comprising the administration to a patient of aneffective amount of modafinil.
 2. Process according to claim 1comprising the oral administration of 1 to 100 mg of modafinil par kg ofbody weight.
 3. Process as claimed in claim 1 for reducing the number ofapneas occurring during sleep apnea syndromes.